The over-arching objective of this project is to further our understanding of leptin's role in fat metabolism of humans. Leptin is a type-I cytokine secreted by adipocytes that binds to Jak/Stat receptors in the central nervous system. Leptin administration typically leads to reduction in appetite and mobilization of stored lipid, however leptin also has effects on reproduction, development, immune function, and bone density. Intense research interest has been focused on leptin (~1000 publications/year since its discovery in 1994), undoubtedly because of its potential as a drug to combat the obesity epidemic. Because leptin's actions are complex, leaders in the field have called for an evolutionary approach to understanding leptin's function. That is, if we can understand leptin's function in 'lower'vertebrates, we can better understand and predict its function in humans (similar to the approach of squid axon, shark rectal gland, etc.). Here we propose to study leptin's effects on protein expression and development in the model organism zebrafish. The specific aims of the proposal are: 1) to test the hypothesis that leptin is essential for normal development in early zebrafish embryos and 2) to test the hypothesis that leptin function is conserved between mammals and adult zebrafish. A suite of techniques, including recombinant protein production, immunoblotting, immunocytochemistry, in situ hybridization, high-speed digital videography, and morpholino antisense oligonucleotides will be employed. Results from the proposed studies should lead to greater understanding of leptin's role in humans and to possible therapies for human obesity. PUBLIC HEALTH RELEVANCE: This proposal investigates leptin's effects on zebrafish development and adult physiology. Results from these experiments may lead to improved understanding of and therapy for human obesity.